The etiology of psychiatric disorders such as autism and schizophrenia has been linked to abnormal development of forebrain components including the basal ganglia. Additionally, disruptions of basal ganglia function are seen in both Parkinson's and Huntington's disease. Given such an involvement, treatment and prevention of these debilitating conditions could be facilitated by elucidation of the developmental mechanisms governing basal ganglia formation. Previous studies of the Dlx ("Distal-less like homeobox") genes have revealed that several family members are key regulators of forebrain development. Mice that lack Dlx1 and 2 gene function exhibit a loss of specific cell types within the striatum, while deletion of Dlx5 and 6 results in exencephaly. In wild type animals, Dlx expression continues through advanced stages of embryogenesis, after the first manifestation of the mutant phenotype. Analysis of any late stage defects is precluded, however, by the early lethality of the mutants. The problem of early mortality can be circumvented through the use of the Cre/loxP system, which allows regulated deletion of gene function in specific tissues at distinct points in development. I will use the Cre/loxP system to knock out individual Dlx genes solely in the telencephalon, to gain insight into the function of the Dlx genes in the terminal stages of vertebrate forebrain development. Through the use of RNA in situ hybridization, immunohistochemistry, and histological staining methods, l will determine the gross anatomical organization, cellular composition, and state of differentiation of the mutant basal ganglia. Additionally, I will undertake a characterization of the molecular effects of Dlx mutation through analysis of the expression patterns of additional genes with known functions in forebrain development. The long-term goal of these studies is to establish a cadre of mutants that will collectively serve to model human neurological disorders, thus allowing identification of the underlying causative agents.